US6632599B1 - Detection and determination of solid phase-associated factors - Google Patents
Detection and determination of solid phase-associated factors Download PDFInfo
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- US6632599B1 US6632599B1 US09/215,209 US21520998A US6632599B1 US 6632599 B1 US6632599 B1 US 6632599B1 US 21520998 A US21520998 A US 21520998A US 6632599 B1 US6632599 B1 US 6632599B1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/554—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being a biological cell or cell fragment, e.g. bacteria, yeast cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/295—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Chlamydiales (o)
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/81—Packaged device or kit
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/962—Prevention or removal of interfering materials or reactants or other treatment to enhance results, e.g. determining or preventing nonspecific binding
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/968—High energy substrates, e.g. fluorescent, chemiluminescent, radioactive
Definitions
- the present invention relates to procedures for the detection or for the determination of solid phase-associated factors, which are multiply associated with the same solid phase.
- the sample is brought into contact with a transmitter particle, on which at least one ligand having binding affinity for a solid phase-associated factor and a transmitter are immobilized, and a receiver particle, on which at least one ligand having binding affinity for said solid phase-associated factor and a receiver is immobilized, and then the signal is determined which results when transmitter and receiver are brought sufficiently close to one another.
- the invention relates to the detection of cell surface receptors which can be used for the typing of cells or for the determination of cell activation states. It is thus possible to replace the hitherto widely customary flow cytometry by a more simple procedure.
- the differentiation of blood cells is a routinely used and important procedure in diagnostics. It is based, inter alia, on the fact that different cell types are characterized by different surface antigens, such as, for example, membrane proteins of the integrins family (Hynes R O. Integrins: a family of cell surface receptors. Cell 1987; 48: 549-554) (incorporated herein by reference). Most of these membrane proteins are designated by CD numbers (cluster designation numbers).
- Membrane proteins can also only be exposed on the surface after stimulation of the cells or secreted by fusion of intracellular vesicles with the surface, such as, for example, proteins from the selectins group (Bevilacqua M P and Nelson R M. Endothelial-Leukocyte adhesion molecules in inflammation and metastasis. Thromb. Haemost. 1993; 70: 152-154) (incorporated herein by reference).
- GMP-140 P selectin; DC62P
- GMP-140 P selectin; DC62P
- characteristic complexes of receptors of cells and ligands can result, such as, for example, on activated platelet complexes of the glycoproteins GP Ib/IX or GP IIb/IIIa, which bind von Willebrand factor or fibrinogen (see, for example, Clemetson K J. Biochemistry of platelet membrane glycoproteins, Prog. Clin. Biol. Res. 1988; 283:33-75) (incorporated herein by reference).
- phosphatidylserine-containing lipid membranes to which clotting factors or other phospholipid-binding protein (for example from the annexins family) can bind, are also exposed on platelets.
- Labels used are substances known per se to the person skilled in the art, in particular chemiluminescent compounds (for a general survey see, for example, Michelson, A. D. and Barnard, M. R., U.S. Pat. No. 5,552,290) (incorporated herein by reference).
- the invention was therefore based on the object of making available an alternative to the previously customary flow cytometry methods, which allows the determination of cell surface antigens in a homogeneous, immunochemical procedure.
- a number of homogeneous, immunochemical procedures for the determination of antigens and antibodies are already known, such as, for example, the FRAT 1 System (Syva), the EMIT 1 System, enzyme channeling immunoassays, fluorescence energy transfer immunoassays (FETI, e.g. TRACE 1 Technology; CIS bio International), enzyme inhibitor immunoassays (Hoffmann LaRoche, Abbott Laboratories) or fluorescence polarization immunoassays (Dandlicker).
- FRAT 1 System Syva
- EMIT 1 System enzyme channeling immunoassays
- FETI fluorescence energy transfer immunoassays
- FETI fluorescence energy transfer immunoassays
- Hoffmann LaRoche Abbott Laboratories
- fluorescence polarization immunoassays Fluorescence polarization immunoassays
- SPA scintillation proximity assay
- This radiation only has a range of a few micrometers in aqueous solutions, so that in dilute suspensions which contain both bead types, only a few beads of the one type are found in sufficiently close to beads of the other type. As a result, all in all only a small fluorescence signal can result.
- an aggregation of the beads takes place which brings many of the beads of the first type (tritium beads) into the vicinity of beads of the second type (fluorophore beads), so that an altogether higher signal results. The resulting signal is detected in a scintillation counter.
- transmitter and receiver particles can be bound to a solid phase-associated factor which is multiply solid phase-associated such that the spatial vicinity necessary for the energy transfer is achieved independently of the size of the solid phase or, in other words, that the greatest distance between transmitter particles and receiver particles at which energy transfer can still take place is not exceeded.
- the solid phase can be, for example, a cell and the solid phase-associated factor can be, for example, a cell surface antigen.
- the present invention therefore relates to a procedure for the detection or for the determination of a solid phase-associated factor F, which is multiply associated with the same solid phase, in a sample.
- the sample is brought into contact with a first stable complex, consisting of at least one ligand L, which has binding affinity for F, and a transmitter T, as well as a second stable complex, consisting of at least one ligand L, which has binding affinity for F, and a receiver R, such that complexes F-L-T and F-L-R are formed.
- the signal is determined which results when T and R are sufficiently close to one another.
- the present invention additionally relates to a procedure for the simultaneous detection or for the simultaneous determination of at least one first solid phase-associated factor Fx and a second solid phase-associated factor Fy, where Fx and Fy are associated with the same solid phase, in a sample.
- the sample is brought into contact with at least one first stable complex, consisting of at least one ligand Lx which has binding affinity for Fx, and a transmitter T, and also a second stable complex, consisting of at least one ligand Ly which has binding affinity for Fy, and a receiver R, such that complexes Fx-Lx-T and Fy-Ly-R are formed.
- the signal is determined which results when T and R are sufficiently close to one another.
- the stable complexes L-T, L-R, Lx-T or Ly-R comprise in each case particles, L or Lx being immobilized together with T on a first particle and L or Ly being immobilized together with R on a second particle.
- the solid phase is a cell, for example an erythrocyte, leucocyte, granulocyte, lymphocyte, monocyte, thrombocyte, or a cell from another tissue or organ.
- the term cell can also mean a prokaryotic or eukaryotic exogenous cell, such as a bacterium or parasite, or alternatively a subcellular parasite, for example a virus.
- Solid phase-associated factors are to be understood as meaning both factors which are integrated into the solid phase and those factors which are not integrated into the solid phase, but are associated with it on account of other interactions.
- a possible sample material is, for example, body fluid, tissue extract or ex-vivo cultures.
- Body fluids here are preferably blood, synovial fluid, cerebrospinal fluid, ascites or urine, particularly preferably whole blood or platelet-rich plasma.
- the present invention furthermore relates to a procedure in which F, Fx and/or Fy is an integral membrane protein, a membrane-associated protein, a glycostructure or a lipid.
- the integral membrane protein can in this case be, for example, an integrin, selectin, a protein from the MHC complex or another known protein according to the cluster designation.
- Membrane-associated proteins are not integrated into the membrane, but detectable on the surface via specific ligand/receptor interactions, such as, for example, fibrinogen on fibrinogen receptors, antibodies against membrane proteins, complement factors or lectins against carbohydrate structures on the membrane surface and/or membrane proteins or processed antigen in the MHC complex on antigen-presenting cells.
- the membrane-associated proteins are furthermore proteins which are detectable on the surface via electrostatic interactions, such as, for example, active enzymes of the clotting system or proteins from the annexins family.
- the lipids according to the invention are substances known to the person skilled in the art from the acylglycerols, phosphoglycerides, sphingolipids, waxes, terpenes, steroids and/or prostaglandins group.
- the composition of the phospholipids of the surface membrane is preferentially detected by binding affinitive ligands, such as proteins from the annexins family, or by binding affinitive proteins of the clotting system such as, for example, activated protein C or protein S.
- the present invention additionally relates to procedures in which the ligand binds to F, Fx or Fy via a mediatory binding component.
- the present invention furthermore relates to procedures in which L, Lx or Ly is bound to particles via a biotin-avidin bridge.
- L, Lx or Ly can be an antibody, antigen, lectin, coenzyme, apoprotein, ligand of a receptor, substrate analog or annexin.
- an energy transfer takes place between the transmitter T and the receiver R.
- This can be effected, for example, by radioactive processes, or by excitation of photosensitive dyes and direct or indirect electron transfer caused thereby, for example by means of activated oxygen.
- the energy transfer in the receiver particle leads to a reaction, for example an emission of luminescence, preferentially chemiluminescence, or fluorescence, which is detectable and a measure of the spatial vicinity of transmitter and receiver particles.
- damping substances such as, for example, dyes or antioxidants
- the procedure according to the invention can be used, for example, for the characterization of cell types, subgroups or activation states of cells, and the detection of surface markers or surface antigens, for example neoepitopes in the context of tumor formation on cells. It can also be used for the typing of tissues or the characterization of tissue compatibility.
- the present invention also relates to the identification of exogenous cells, generally pathogens, such as bacteria.
- the process according to the invention is very particularly suitable for the identification of chlamydia.
- Transmitter and “receiver” in the context of the present invention are understood as meaning members of classes of biological or chemical substance which can interact with one another in spatial vicinity, e.g. in the form of energy donors and energy recipients, such as, for example, photosensitizers and chemiluminescers (EP-0 515 194; Ullman et al. (1996) Clinical Chemistry 42:1518-1526), photosensitizers and fluorophores (WO 95/06877; Bystrak et al. (1995) Anal. Biochem. 225:127-134), or radioactive iodine 125 and fluorophores (S. Udenfriend et al. (1985) Proc. Natl. Acad. Sci.
- An interaction between transmitter and receiver is, in particular, an energy transfer —i.e. the direct transfer of energy between transmitter and receiver, for example by means of light or electron radiation, and also by means of reactive chemical molecules.
- the idea of an interaction between transmitter and receiver is also understood as meaning enzyme cascades.
- the substances are enzymes, of which at least one yields the substrate for another.
- the activity of a substance is inhibited or increased by one or more others, for example the inhibition of or increase in enzyme activity or the inhibition of, increase in or change (e.g. wavelength shift) in the light emitted by the affected substance.
- transmitter and receiver takes place when these are spatially adjacent, i.e., for example, within a distance range of a few ⁇ m, in particular within a distance range of less than 600 nm, preferably less than 400 nm, very particularly preferably less than 200 nm.
- the interaction between transmitter and receiver is effected as an energy transfer, e.g. by means of the following methods, the references to which are incorporated herein by reference:
- radioactive ⁇ -radiation see Hart & Greenwald (1979) Molecular Immunology 16:265-267 and Udenfriend et al. (1985) Proc. Natl. Acad. Sci. 82:8672-8676
- the surface of the particles has been further modified after their preparation and/or the particles are covered by one or more covalently or adsorptively bound layers or shells, for example of proteins, carbohydrates, lipophilic substances, biopolymers, organic polymers or mixtures thereof, in order, for example, to achieve improvements with respect to suspension stability, storage stability, shaping stability or resistance to UV light, microbes or other agents having a destructive action.
- the modifications and coverings can likewise be used here to reduce or to suppress the nonspecific binding to surfaces of reaction vessels and to those of protein constituents such as, in particular, proteins (e.g. albumin or antibody) or cell constituents (for example phospholipids or nucleic acids).
- the modifications and coverings are used to increase or to lower the hydrophobicity of the particle surface or the loading of the surface of the particles.
- a further embodiment of the process according to the invention comprises employing, as transmitters or receivers, photosensitizers, for example acetone, benzophenone, 9-thioxanthone, eosin, 9,10-dibromoanthracene, chlorophyll, Buckminsterfullerene, Methylene Blue, Rose Bengal, porphyrins, phthalocyanines and/or their derivatives, and as chemiluminescent compounds, for example, olefins, 9-alkylidenexanthans, 9-alkylidene-N-alkylacridans, enol ethers, enamines, aryl vinyl ethers, dioxenes, arylimidazoles and/or lucigenin and it being possible for the singlet oxygen generated by the photosensitizer to activate the chemiluminescent compounds to emit light.
- photosensitizers for example acetone, benzophenone, 9-thioxanthone,
- the chemiluminescent compounds emit light in the wavelength ranges over 300 nm.
- the fluorescence of plasma falls rapidly in the range from 500 nm and can be neglected above 550 nm.
- the chemiluminescent compounds according to the invention can also be brought into contact with fluorophores which can be excited by the activated chemiluminescent compounds and emit at higher wavelengths.
- a further embodiment of the procedure according to the invention comprises employing photosensitizers and fluorescent compounds as substances and it being possible for the fluorescent compound for light emission to activate or, in a quench process, to suppress the light emission of the singlet oxygen generated by the photosensitizer.
- procedures according to the invention are preferred which comprise the use of fluorescent compounds which are subject to photooxidation—photobleaching—by reaction with singlet oxygen, such as, for example, 1,3-diphenylisobenzofuran, or react with singlet oxygen as photoactive precursors to give fluorophores, such as, for example, oxene umbelliferyl ethers or umbelliferyl selenides.
- FIG. 1A illustrates identical antibodies on transmitter and receiver particles.
- FIG. 1B illustrates different antibodies on transmitter and receiver particles.
- a solid phase in the sense of the present invention for example a cell
- a solid phase-associated factor for example a surface epitope
- two different binding components do not necessarily have to be applied to transmitter and receiver particles.
- the same binding component on transmitter and receiver particles is thus sufficient for the detection of certain solid phase-bound factors, for example of antigens or ligands.
- the determination of certain cell types or the determination of certain activation states which accompany the expression of certain factors on the cell surface is thus made possible.
- the radius of the effective energy transfer must be so low that it can really only take place between very closely adjacent transmitter and receiver particles and the polyvalence of the solid phase itself—for example on account of the great accummulation of one of the binding components, leads to no undesired energy transfer.
- the radius of the effective energy transfer is dependent on the detection system used, and the reduction of this radius can be achieved by altering the nature of the particles or affecting the quench effect of the surrounding solution by means of additives known to the person skilled in the art.
- FIG. 1A transmitter and receiver particles were loaded with the same antibody against GP IIb.
- signal transmission is a measure of the quantity (the frequency on the surface) of a certain surface epitope, in the present example of GP IIb.
- T4 and T8 for the differentiation of lymphocytes, IgE receptors for the detection of allergic reactions, or the determination of histocompatibility antigens in cell extracts or lyzates before transplantation of organs or tissues, or the diagnosis of cell activation states by the detection of changes in consecutive or newly presented integral membrane proteins, of surface-active proteins or of neoepitopes.
- transmitter and receiver particles are loaded with two different ligands, for example the transmitter with antibodies against GP IIb and the receiver with antibodies against GP IIIa, then a signal is only generated when the two different ligands are sufficiently close to one another, i.e. in the present example when the complete fibrinogen receptor GP IIb/IIIa is present on the cell.
- complexes whose detection is of interest can consist, for example, of the following components: of clotting enzymes and their cofactors, or of clotting enzymes and physiologically active surfaces, or of components of the MHC (major histocompatibility complex), or of T3, Tr and T4 or T8 on immune cells, or of components of the complement system, such as, for example, the MAC (membrane attack complex), consisting of the complement factors C5b, C6, C7, C8, C9 and vitronectin (T protein).
- MAC membrane attack complex
- the process according to the invention can also be used for simplifying the detection of microorganisms.
- the principle of the present invention is illustrated as exemplified by chlamydia detection, it being immediately clear to the person skilled in the art that the invention is not limited to the detection of this microorganism.
- a multiplicity of methods for the detection of chlamydia has already been described, such as, for example, the culturing of chlamydia in cell cultures, immunoassays or nucleic acid (DNA detection procedures).
- the immunological test procedures are aimed, for example, at the specific detection of chlamydia for making a clinical diagnosis.
- Two methods have essentially been used here: a first in which enzyme-labeled antibodies were measured in the chlamydia antigen released beforehand; a second in which chlamydia fixed to slides were detected microscopically by means of fluorescence-labeled antibodies using unliberated antigen still bound to chlamydia.
- the chlamydia antigens to be detected must be extracted. This is carried out with the aid of detergents (see, for example, EP-0 392 865) (incorporated herein by reference) or with the aid of detergents under simultaneous alkaline conditions (see, for example, EP-0 402 396) (incorporated herein by reference).
- Other processes need, optionally additionally to the extraction, washing steps during the course of the test in order to remove unbound chlamydia-specific antibodies (see, for example, U.S. Pat. No. 4,497,899) (incorporated herein by reference).
- a further previously known procedure necessitates heating to 100° C. for 15 min in order to release chlamydia-specific antigens for detection (EP-0 371 049) (incorporated herein by reference).
- Other different procedures extract antigens, form immune complexes, which then have to be filtered off for detection, via specific antibodies, followed by washing steps to remove unbound antibodies (EP-0 451 687) (incorporated herein by reference).
- a further previously known process transports enzymatically released antigens through a porous membrane in which chlamydia-specific antibodies bind to the released antigens and are detected by means of subsequent steps (EP-0 444 303) (incorporated herein by reference).
- the present invention therefore also relates to a procedure according to which chlamydia cells contained in a sample are brought into contact with transmitter and receiver particles, both types of particles in each case carrying at least one ligand having binding affinity for chlamydia cells and the transmitter particles additionally carrying a transmitter and the receiver particles additionally carrying a receiver. The signal is then determined which results when transmitter and receiver are brought sufficiently close to one another.
- sensitizer and chemiluminescer particles were used according to LOCI technology.
- the particles were obtained from the Syva Business Unit, Behring Diagnostics Inc., San Jose.
- the preparation instructions followed the procedures described in EP Patent 0 515 194 and in the references Ullman et al. Clin Chem. (1996) 42:9, 1518-1526 and Natl. Acad. Sci. (1994) 91, 5426-5430.
- Acceptor particles were coated with a lipopolysaccharide (LPS)-specific antibody.
- LPS lipopolysaccharide
- the coating procedure is described in Ullman et al. (1996) 42:9, 1518-1526. Parallel to this, a specific antibody against the major outer membrane protein (MOMP) was labeled with biotin.
- Sensitizer particles were coated with avidin. These procedures are also described in Ullman et al. (1996) 42:9, 1518-1526 (incorporated herein by reference).
- the chlamydia, the acceptor beads, the biotinylated antibody and the sensitizers were diluted in the following buffer: 0.1 M tris HCl; 0.5 M NaCl; 0.025 M EDTA; 1.6% BTA (pH 7.6).
- chlamydia suspension 25 ⁇ l of chlamydia suspension were mixed with 25 ⁇ l of acceptor beads (100 ⁇ g/ml) and incubated at 37° C. for 6 min. 35 ⁇ l of biotinylated antibodies (10 ⁇ g/ml) were then added and the mixture was again incubated at 37° C. for 6 min. 50 ⁇ l of sensitizer particles (400 ⁇ g/ml) were then added and the emitted chemoluminescence was determined in a luminometer.
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Abstract
Description
Claims (29)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19756782A DE19756782A1 (en) | 1997-12-19 | 1997-12-19 | Detection and determination of solid phase associated factors |
DE19756782 | 1997-12-19 |
Publications (1)
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US6632599B1 true US6632599B1 (en) | 2003-10-14 |
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US09/215,209 Expired - Lifetime US6632599B1 (en) | 1997-12-19 | 1998-12-18 | Detection and determination of solid phase-associated factors |
Country Status (7)
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US (1) | US6632599B1 (en) |
EP (1) | EP0924522B1 (en) |
JP (1) | JP4276320B2 (en) |
AT (1) | ATE336722T1 (en) |
CA (1) | CA2256087C (en) |
DE (2) | DE19756782A1 (en) |
ES (1) | ES2268747T3 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009066131A1 (en) * | 2007-11-19 | 2009-05-28 | Mahmoud Rafea | Methods for preparation of vaccines, laboratory kits, and treatment components |
US20110091978A1 (en) * | 2009-10-21 | 2011-04-21 | Siemens Healthcare Diagnostics Inc. | Stabilization of signal generation in particles used in assays |
US20110237462A1 (en) * | 2008-12-04 | 2011-09-29 | Fujifilm Corporation | Immobilization substrate and method for producing the same |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6682903B2 (en) | 2000-10-14 | 2004-01-27 | Alex M. Saunders | Ligand based solution assay for low concentration analytes |
JP5047783B2 (en) * | 2004-05-13 | 2012-10-10 | サントル・ナシオナル・ドゥ・ラ・ルシェルシュ・シアンティフィーク(セーエヌエールエス) | Device for binding a target entity to a decoy entity and detection method using the device |
KR102034381B1 (en) | 2018-05-04 | 2019-10-18 | 고려대학교 산학협력단 | The Multilayered Nanowire Complex and The Fabrication Method Of The Same |
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EP0371049A1 (en) | 1987-07-14 | 1990-06-06 | Univ Manchester | Method for the diagnosis of infections with detection of lipopolysaccharide antigens. |
EP0392865A1 (en) | 1989-04-14 | 1990-10-17 | Unilever Plc | Extraction procedure |
EP0402396A1 (en) | 1988-02-29 | 1990-12-19 | Kallestad Diagnostics Inc | Chlamydia assay employing base treatment. |
EP0444303A2 (en) | 1990-03-01 | 1991-09-04 | Becton, Dickinson and Company | Detection of chlamydia by flow-through assay |
US5047321A (en) * | 1988-06-15 | 1991-09-10 | Becton Dickinson & Co. | Method for analysis of cellular components of a fluid |
EP0451687A2 (en) | 1990-04-12 | 1991-10-16 | Miles Inc. | Chlamydia half-sandwich immunoassay |
EP0515194A2 (en) | 1991-05-22 | 1992-11-25 | BEHRINGWERKE Aktiengesellschaft | Assay methods utilizing induced luminescence |
US5340716A (en) * | 1991-06-20 | 1994-08-23 | Snytex (U.S.A.) Inc. | Assay method utilizing photoactivated chemiluminescent label |
WO1995006877A1 (en) | 1993-09-03 | 1995-03-09 | Behringwerke Ag | Fluorescent oxygen channeling immunoassays |
US5527684A (en) | 1991-01-28 | 1996-06-18 | Cis Bio International | Method of measuring the luminescence emitted in a luminescent assay |
US5536642A (en) * | 1993-09-09 | 1996-07-16 | Barbera-Guillem; Emilio | Diagnostic and prognostic methods for solid non-lymphoid tumors and their metastases |
US5552290A (en) | 1994-11-14 | 1996-09-03 | University Of Massachusetts Medical Center | Detection of procoagulant platelet-derived microparticles in whole blood |
US5709994A (en) * | 1992-07-31 | 1998-01-20 | Syntex (U.S.A.) Inc. | Photoactivatable chemiluminescent matrices |
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1997
- 1997-12-19 DE DE19756782A patent/DE19756782A1/en not_active Ceased
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1998
- 1998-11-20 AT AT98122039T patent/ATE336722T1/en active
- 1998-11-20 ES ES98122039T patent/ES2268747T3/en not_active Expired - Lifetime
- 1998-11-20 EP EP98122039A patent/EP0924522B1/en not_active Expired - Lifetime
- 1998-11-20 DE DE59813689T patent/DE59813689D1/en not_active Expired - Lifetime
- 1998-12-15 CA CA002256087A patent/CA2256087C/en not_active Expired - Fee Related
- 1998-12-18 JP JP36066198A patent/JP4276320B2/en not_active Expired - Fee Related
- 1998-12-18 US US09/215,209 patent/US6632599B1/en not_active Expired - Lifetime
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009066131A1 (en) * | 2007-11-19 | 2009-05-28 | Mahmoud Rafea | Methods for preparation of vaccines, laboratory kits, and treatment components |
US20110237462A1 (en) * | 2008-12-04 | 2011-09-29 | Fujifilm Corporation | Immobilization substrate and method for producing the same |
US20110091978A1 (en) * | 2009-10-21 | 2011-04-21 | Siemens Healthcare Diagnostics Inc. | Stabilization of signal generation in particles used in assays |
US8153442B2 (en) | 2009-10-21 | 2012-04-10 | Siemens Healthcare Diagnostics Inc. | Stabilization of signal generation in particles used in assays |
Also Published As
Publication number | Publication date |
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ES2268747T3 (en) | 2007-03-16 |
CA2256087C (en) | 2009-02-17 |
JPH11242029A (en) | 1999-09-07 |
EP0924522B1 (en) | 2006-08-16 |
EP0924522A3 (en) | 2000-06-07 |
JP4276320B2 (en) | 2009-06-10 |
EP0924522A2 (en) | 1999-06-23 |
DE59813689D1 (en) | 2006-09-28 |
CA2256087A1 (en) | 1999-06-19 |
ATE336722T1 (en) | 2006-09-15 |
DE19756782A1 (en) | 1999-06-24 |
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